Kappa and delta opioid receptor signaling is augmented in the failing heart

Abstract The opioidergic system, an endogenous stress pathway, modulates cardiac function. Furthermore, opioid peptide and receptor expression is altered in a number of cardiac pathologies. However, whether the response of myocardial opioid receptor signaling is altered in heart failure progression is currently unknown. Elucidating possible alterations in and effects of opioidergic signaling in the failing myocardium is of critical importance as opioids are commonly used for pain management, including in patients at risk for cardiovascular disease. A hamster model of cardiomyopathy and heart failure (Bio14.6) was used to investigate cardiac opioidergic signaling in heart failure development. This study found an augmented negative inotropic and lusitropic response to administration of agonists selective for the kappa opioid receptor and delta opioid receptor in the failing heart that was mediated by a pertussis toxin-sensitive G-protein. The augmented decrease in cardiac function was manifested by increased inhibition of cAMP accumulation and the amplitude of the systolic Ca2+ transient. Furthermore, increased depression of cardiac function and of two important second messengers, cAMP and intracellular Ca2+ , were independent of changes in cardiac opioid peptide or receptor expression. Thus, the cardiomyopathy-induced failing heart experiences increased cardiac depressant effects following opioid receptor stimulation which could exacerbate diminished cardiac function in end-stage heart failure. As cardiac function is already depressed in heart failure patients, administration of opioids could exacerbate the degree of cardiac dysfunction and worsen disease progression.